Cytokinetics, Inc. is a clinical-stage biopharmaceutical company focused on the discovery and development of novel small molecule therapeutics that modulate muscle function for the potential treatment of serious diseases and medical conditions. A central effort is to develop novel skeletal muscle activators to treat diseases that result in skeletal muscle weakness and fatigue. The company has developed a direct activator of fast skeletal muscle fibers, CK-2017357. This compound binds to the troponin complex of the sarcomere and sensitizes muscle to nerve stimulation, increasing force development at sub-maximal stimulation. A first time in human (FTIH) study of this compound was initiated in healthy volunteers in the United States in June 2009. Direct activation of the skeletal muscle sarcomere is a unique drug mechanism and has potential applications to a large number of diseases where muscle weakness is a feature; these include serious neuromuscular disorders, rehabilitation recovery, intermittent claudication (cramping pains in the legs caused by peripheral arterial disease), muscle wasting (cachexia) associated with cancer, heart failure or other diseases, and the frailty associated with aging (also known as sarcopenia). The objective of this project is to demonstrate a clinical proof-of-concept in myasthenia gravis (MG), a serious autoimmune neuromuscular disorder caused by auto-antibodies to the acetylcholine receptor of muscle. Preclinical evidence suggests that muscle sensitization with CK-2017357 may directly reduce weakness and fatigue in these patients where neuromuscular transmission is limiting. The specific aims for this project are two-fold: (i) to gather convincing preclinical evidence of efficacy in models of MG by measuring muscle function in a rat model of MG (experimental autoimmune MG model caused by immunization of rats with purified acetylcholine receptor protein) and (ii) to establish proof-of-concept in a Phase 2A trial of patients with MG. Physical performance will be evaluated in MG patients after a single dose or multiple doses. These studies will be enabled by Cytokinetics' FTIH Phase I clinical trial in healthy volunteers. CK-2017357 represents a first in class functional activator of skeletal muscle with potentially broad therapeutic application to conditions with muscle weakness. Positive data from a Phase 2A trial in MG would encourage Phase 3 trials in MG and other neuromuscular disorders as well as provide momentum to examine this promising therapeutic strategy in other indications. PUBLIC HEALTH RELEVANCE: We have developed a first in class compound, CK-2017357, which can directly increase force in skeletal muscle. The research detailed in this application will provide evidence that CK-2017357 can increase muscle force in the severe neuromuscular disease, myasthenia gravis and help patients cope with the muscle weakness that occurs in this disease.